1. Field of the Invention
The composition is comprised of a 0.005%-2.0% weight/volume (w/v) chlorine dioxide source (sodium chlorite, chlorite ion, stabilized chlorine dioxide or similar) and may take the form of an oral paste, gel, rinse, spray, powder, tray, varnish or similar, to facilitate the healing of osteonecrosis of the jaw symptoms (including but not limited to necrotic bone lesions, inflammation and infection) and to prevent the development of osteonecrosis of the jaw. The method is the application of the composition in the oral cavity and all other areas of the body affected by osteonecrosis of the jaw to produce an antimicrobial effect, sanitize, debride, and penetrate, eliminate and control biofilms associated with osteonecrosis of the jaw, to facilitate the healing of osteonecrosis of the jaw symptoms and prevent the development of osteonecrosis of the jaw. The method may be applied daily or continuously as a treatment or prevention regimen for osteonecrosis of the jaw.
2. Description of Related Prior Art
Osteonecrosis is characterized by the formation of dead (necrotic) bone in various bones in the body, such as the femoral head or the jaw (mandible and/or maxilla). Pain and edema of surrounding tissue may accompany or precede this necrotic bone development.
Some forms of osteonecrosis are believed to develop due to either 1) decreased blood flow to bone which occurs as a result of a traumatic event or 2) non-traumatic factors. While the pathophysiology of all forms of osteonecrosis is currently unknown, some factors may potentially contribute to its development. These include bisphosphonate use, a compromised immune system, age, corticosteroid use, and tissue trauma. However, how these factors might contribute to the development of osteonecrosis is also unknown and still under investigation (AAMOS, 2007; Mariotti, 2008; Bejar et al., 2005).
Bisphosphonates are a class of drugs prescribed for diseases involving deleterious bone resorption, such as osteoporosis, bone cancer, or Paget's disease. In general, these drugs may be administered orally, intravenously, or parenterally and act by targeting osteoclasts in bone to inhibit and disrupt the bone resorption activity. The resulting function depends on the specific chemical structure of the bisphosphonate compound. Bisphosphonates are inorganic pyrophosphate analogues that contain two phosphonate groups along with R1 and R2 variable side chains all bound to a central carbon. Bisphosphonates localize to bone due to two phosphonate groups bonding to hydroxyapatite crystals and the variable group at the R1 position (which may be a hydroxyl group that has a higher affinity for calcium than a halogen). After bone localization, the antiresorptive potency of the bisphosphonate is also dependent on the three-dimensional R2 side chain conformation, the overall chemical structure, and both phosphonate groups (Russell, 2007).
Two subclasses of bisphosphonates with differing chemical structures and functions are: 1) nonaminobisphosphonates and 2) aminobisphosphonates, which contain an amino-nitrogen atom at the R2 position. As these compounds lack an amino-nitrogen atom, nonaminobisphosphonates are more similar to inorganic pyrophosphate. Hence, osteoclasts “metabolically incorporate” nonaminobisphosphonates to form nonhydrolyzable adenosine triphosphate analogues, which in turn results in apoptosis of the osteoclast (Russell, 2007). Despite this occurrence, the presence of the amino-nitrogen atom at the R2 position transforms aminobisphosphonates into more potent antiresorptive compounds than nonaminobisphosphonates (up to 10000-fold more potent). The main function of aminobisphosphonates involves inhibition of a key component of the mevalonate pathway (cholesterol synthesis), specifically the enzyme farnesyl diphosphonate synthase. Disruption of cholesterol synthesis is deleterious to various cellular activities in the osteoclast, which arrests osteoclast activity and ultimately bone resorption (Woo et al., 2006; Russell, 2007).
Since 2003, bisphosphonate-associated osteonecrosis of the jaw (ONJ) has been observed in patients receiving bisphosphonate therapy. ONJ is clinically diagnosed when an individual on a bisphosphonate drug regimen has necrotic bone lesion(s) on the jaw (mandible and/or maxilla) which persists for more than 8 weeks (without head or neck radiation being received by the patient simultaneously) (Estilo et. al., 2008; Woo et. al., 2006). There is no standard and reliable test to diagnose, anticipate or predict ONJ development. Therefore, ONJ is identified and diagnosed by the clinical definition after the onset and persistence of symptoms, through visual observation by the clinician and/or the use of medical imaging such as radiographs (Mariotti, 2008; Khosla et. al., 2007). Clinical staging of ONJ has been proposed to characterize the progression. At Risk stage comprises of individuals that exhibit no symptoms but are receiving either intravenous or oral bisphosphonates. Stage 1 involves the initial appearance of necrotic bone on the jaw but lacks the presence of infection. Stage 2 includes both the presence of necrotic bone on the jaw and infection, with associated pain. Stage 3 involves necrotic bone on the jaw, infection, pain “and one or more of the following: pathologic fracture, extraoral fistula, or osteolysis extending to the inferior border” (Ruggiero, 2008).
Patients receive bisphosphonates as primary and secondary therapies for diseases relating to abnormal bone resorption. Such patient populations include: 1) individuals at high risk for developing and diagnosed with osteoporosis, 2) bone cancer and multiple myeloma patients, 3) cancer patients at high risk for bone metastases, and 4) patients with Paget's disease (Ruggiero and Drew, 2007). Bisphosphonate therapies may be taken long-term (months to years), as is the case for the prevention and treatment of osteoporosis, where these drugs may be taken for up to a decade or more. Furthermore, bisphosphonates for cancer treatments may also be indicated over months as well. Since an individual may receive bisphosphonates over many months or years, a need exists for a long-term ONJ treatment and preventative that is safe and efficacious throughout the term of bisphosphonate therapy.
Since the pathophysiology of ONJ is unknown and there are no biomarkers to the development of the disease, the options for prevention are limited. One key prevention recommendation, however, is “to maintain good oral hygiene” and to receive a dental examination before beginning bisphosphonate therapy. Other recommended steps include having any needed invasive dental procedures prior to beginning a bisphosphonate regime and/or stopping bisphosphonate use prior to or during execution of the dental procedures (AAOMS, 2007; Khan, 2008). Refraining from smoking and minimizing alcohol consumption during bisphosphonate usage is also advised (Khan, 2008). ONJ preventative strategies vary according to the type of bisphosphonate being administered (intravenous versus oral) and the duration of use (Khosla, et al., 2007).
There is no standard treatment for ONJ. Currently, treatment is at the discretion of the clinician, dependent on a number of factors including the stage of the condition and duration of bisphosphonate use (Woo et al., 2006; Ruggiero 2008). One treatment involves the use of antibiotics with adjunct application of an anti-microbial oral rinse, such as the standard 0.12% chlorhexidine rinse (Ruggiero, 2008). Various studies examining the use of chlorhexidine with ONJ patients indicate that while it may help stop ONJ progression, it may not lead to assured ONJ resolution in all patients (Estilo et al., 2008). Other suggested treatments include, but are not limited to: hyperbaric oxygen therapy, surgical debridement/resection, halting bisphosphonate therapy, and use of other anti-bacterial oral rinses (AAOMS, 2007; Khosla et al., 2007; Ruggiero, 2008). Some treatments also include surgery, antibiotics, or debridement. The current goals for ONJ treatment are: 1) to preserve the patient's quality of life (through ONJ prevention, managing pain and secondary infection, and/or stopping progression of the condition) and 2) to enable oncology patients continued bisphosphonate use (AAOMS, 2007).
The specific association between bisphosphonates and ONJ development is not known nor has a direct causal link between bisphosphonate usage and the onset of ONJ disease been definitively established (ADA Council on Scientific Affairs Expert Panel ONJ, 2008; Mariotti, 2008). Certain factors however are believed to potentially increase an individual's risk for developing ONJ, such as: “1) history of dento-alveolar trauma, 2) duration of bisphosphonate exposure,” and 3) the type and route of bisphosphonate administration such as oral versus intravenous (Ruggiero and Drew, 2007). Thus, ONJ prevalence and incidence are currently being investigated taking these factors into account. For example, one inquiry evaluating ONJ prevalence among oral alendronate users reported an ONJ prevalence rate of 4% in 208 patients (Sedghizadeh, et al., 2009). Furthermore, ONJ incidence in intravenous users may be as high as 12% as opposed to a reported 0.01% in oral users (Marder and Marder, 2008). It is also noted that aminobisphosphonates, such as pamidronate and zoledronic acid, are the bisphosphonate subclass most often associated with ONJ occurrence. One study stated that 94% of the reported ONJ patients had received zoledronic acid, pamidronate or a combination of the two drugs (Woo et al., 2006).
The pathophysiology of ONJ is unknown and currently under investigation. Many journal articles and reviews have been published evaluating the possible pathophysiology of this condition. One hypothesis suggested by Woo et al. (2006) is:                “ . . . that bisphosphonate-associated osteonecrosis of the jaws results from marked suppression of bone metabolism that results in accumulation of physiologic microdamage in the jawbones, compromising biomechanical properties. Trauma and infection increase demand for osseous repair that exceeds the capacity of the hypodynamic bone, resulting in localized bone necrosis. The antiangiogenic property of bisphosphonates and other medications and the presence of other comorbid factors may promote the risk for or persistence and progression of this condition.”        
Along with the suppression of bone metabolism due to bisphosphonates, microbial biofilms are also hypothesized to be involved in ONJ. Biofilms are believed to be a source of microbial infection that can lead to development or increase progression of ONJ. According to Donlan and Costerton, “a biofilm is a microbially derived sessile community characterized by cells that are irreversibly attached to a substratum, interface or to each other, are embedded in a matrix of extracellular polymeric substances that they have produced, and exhibit an altered phenotype with respect to growth rate and gene transcription” (Donlan and Costerton, 2002). Multispecies microbial biofilms were recently identified in bone specimens from ONJ lesions of four ONJ patients (Sedghizadeh et al., 2008). Specific pathogens classified in these ONJ biofilms were from genera such as: Fusobacterium, bacillus, actinomyces, staphylococcus, treponemes, and Candida, among others. The bacteria ranged from gram-positive and gram-negative organisms and included aerobes, although anaerobes and facultative anaerobes dominated. Known morphotypes of the Candida species were also apparent in the ONJ biofilm of all four subjects and co-aggregation with bacteria also was observed. Sedghizadeh et al. further observed the absence of eukaryotic cells and the presence of microorganisms in the bone resorption pits of osteonecrotic bone specimens, indicating that microorganisms possibly directly contribute to bone resorption as well. Taken together, the presence of biofilms in ONJ may potentially contribute to development and progression (Sedghizadeh et al., 2008).
The ADA Council on Scientific Affairs Expert Panel on ONJ (2008) mentioned a second hypothesis that the bisphosphonate compounds themselves are toxic to the tissues vulnerable to ONJ development. Preliminary in vitro evidence on oral mucosal cells (human gingival fibroblasts and keratinocytes) indicates that direct application of zoledronic acid has a deleterious effect on the life of these cells (Scheper et al., 2008). Specifically, these cells experience gene-regulated induced apoptosis when zoledronic acid at low concentrations is applied. Apoptotic genes activated by zoledronic acid include TNF, BCL-2, Caspase, IAP, TRAF (Scheper et al., 2008). As a result, direct toxicity to oral mucosal cells by bisphosphonates may also be a factor in ONJ development.
The term chlorine dioxide (ClO2) is widely used in the industry. Those skilled in the art will and do appreciate the various forms or variations thereof which are available to perform certain intended functions and purposes. U.S. Pat. No. 3,271,242 describes a form of stabilized chlorine dioxide and a method of making it which form is particularly useful in carrying out the present invention. The 1979 text Chlorine Dioxide, Chemistry and Environmental Impact of Oxychlorine Compounds, describes (aqueous) stabilized chlorine dioxide as follows:                “The stabilization of chlorine dioxide in aqueous solution was proposed by using perborates and percarbonates. Thus, a stabilized solution of ClO2 would be obtained at pH 6 to 8 by passing gaseous ClO2 into an aqueous solution containing 12% Na2CO3.3H2O2. Other variants are possible. In reality, it seems that in these methods, the chlorine dioxide is practically completely transformed to chlorite. Dioxide is released upon acidification . . . ” [Masschelein, 1979]        
The term ‘peroxy compounds’ may substitute for ‘percarbonates and perborates’, referring to any buffer suitable for maintaining the pH and hence, the stability of the ClO2 in solution. The buffer is a necessary component, as the ClO2 is unstable at low pH. Once the solution reaches low pH or encounters an area of low pH, the stabilized ClO2 is released from solution and available for sanitation and oxidation.
Prior to its use in the 1950s, chlorine dioxide was a known to have bactericidal properties (Masschelein, 1979). In U.S. Pat. No. 2,451,897 Woodward first established use of chlorine dioxide to eliminate the unpalatable taste in shrimp; thereafter, chlorine dioxide began to be used for its oxidative properties in various industries for different applications. Chlorine dioxide has been applied to bleaching cellulose fibers to facilitate the manufacture of wood pulp. Furthermore, chlorine dioxide has been used to disinfect water for public consumption with minimal effect on taste. Chlorine dioxide provides a beneficial alternative over other processes involving the use of ozone and bleach, due to the fact that chlorine dioxide costs less to use, creates less toxicity, and creates fewer chlorinated by-products (Masschelein, 1979).
Biofilm growth is a problem which occurs in dental unit water lines (DUWL). Some of the microbe genera detected in DUWL biofilms are Actinomyces, Bacillus, Mycobacteria, Pseudomonas, Sphingomonas, Staphylococcus, and Streptococcus. Stabilized chlorine dioxide solutions have been previously shown to be an effective decontaminant on biofilms that form in DUWLs. A specific study yielded results that indicated that stabilized chlorine dioxide outperformed alkaline peroxide in managing biofilm growth, by retaining a hetertropic plate count (HPC) value of 0 after 5 days of treatment (Wirthlin et al., 2003).
In oral care products, the use of stabilized chlorine dioxide has been suggested as an active ingredient by a number of patents: U.S. Pat. Nos. 4,689,215; 4,696,811; 4,786,492; 4,788,053; 4,792,442; 4,793,989; 4,808,389; 4,818,519; 4,837,009; 4,851,213; 4,855,135; 4,886,657; 4,889,714; 4,925,656; 4,975,285; 5,200,171; 5,348,734; 5,489,435; 5,618,550. Additionally, the use of stabilized ClO2 has been suggested for the degradation of amino acids in U.S. Pat. No. 6,136,348. The premise for these products is that the stabilized chlorine dioxide will remain as such until it encounters the localized reductions in pH. Reduced pH levels can be a result of low pH saliva or oral mucosa, the accumulation of oral disease-causing bacteria or the presence of plaque biofilms on teeth and epithelial cells. Once released, the now active chlorine dioxide is effective at killing bacteria and oxidizing volatile sulphur compounds (VSCs). VSCs have been shown to enable oral infections and inflammation as well as produce oral malodor. Data have shown dramatic reduction in bacteria after exposures as short as 10 seconds, as set forth in U.S. Pat. No. 4,689,215. Additional data show remarkable decrease in VSCs in expired mouth air; the mechanism is believed to be oxidation of VSCs through the cleavage of the sulfide bonds.
Richter (U.S. Pat. No. 5,738,840) teaches the use of a two part system to deliver molecular chlorine dioxide to the oral cavity. This method relies on the use of a metal chlorite salt mixed with a metal hypochlorite salt (such as sodium hypochlorite) to form molecular chlorine dioxide (between 3 and 200 parts per million (ppm)). The application of this method is to treat halitosis. Madray further instructs on a method to make molecular chlorine dioxide (U.S. Pat. No. 6,231,830). Madray indicates mixing an alkali metal chlorite with an alkali metal iodide to produce molecular chlorine dioxide, but also indicates that these two entities should not be mixed until the chlorine dioxide is necessary, in order to ensure long shelf-life. Madray describes the use of this invention to treat gum disease, acne, and dandruff, along with additional ailments and conditions.
The delivery of chlorine dioxide precursors, such as the chlorite ion, to the mouth is taught by Witt (U.S. Pat. Nos. 6,077,502; 6,132,702; 6,235,269; 6,251,372; 6,264,924; and 6,350,438). Witt teaches the delivery of the chlorite ion to the oral cavity, via various delivery systems including oral rinse, using formulations with minimal chlorine dioxide (50 ppm or less) and at a pH greater than 7. Witt's patents also teach the use of these formulations to treat malodor, gingivitis, periodontitis, osteomyelitis of the jaw, and infectious stomatitis, among other applications.
Doyle (U.S. Pat. No. 6,846,478) teaches that topical oral application of a “safe and effective” amount of the chlorite ion (pH greater than 7 and 0.02-6.0% (w/v)) can control bacteria-mediated diseases and promote whole body health. The inventors claim that periodontal disease may be related to increased risk of developing certain diseases and that the chlorite ion is an antimicrobial that is selective for gram negative anaerobes that cause periodontal diseases (P. gingivalis, B. forsythus, A. actinomycetemcomitans, T. denticola, T. socranskii, F. nucleatum, and P. intermedia). Therefore, Doyle claims that since the chlorite ion prevents “the spread of bacteria” via the oral cavity and thereby helps control systemic oral pathogenic infections that increases risk for these “bacteria-mediated” diseases, the chlorite ion promotes whole body health. Furthermore, Doyle claims the chlorite ion is able to reduce specific biomarkers of these diseases. Doyle cites the chlorite ion's ability to specifically reduce disease risk of atherosclerosis, diabetes, stroke, severe respiratory diseases, bacteremia, and those at risk for delivering pre-term low birth weight babies.
While the prior art teaches various compositions of chlorine dioxide and chlorine dioxide precursors relative to general oral health, gum disease and oral malodor, these sources do not teach the effectiveness of such compositions on biofilms found on the treatment of osteonecrosis of the jaw or preventing the onset of osteonecrosis of the jaw.